Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Trial to Determine Safety and Development of Protective Efficacy After Exposure to Only Pre-erythrocytic Stages of Plasmodium Falciparum



Status:Recruiting
Conditions:Infectious Disease
Therapuetic Areas:Immunology / Infectious Diseases
Healthy:No
Age Range:18 - 50
Updated:4/6/2019
Start Date:June 5, 2017
End Date:December 31, 2020
Contact:Agnes N Mwakingwe, M.D.
Email:agnes.mwakingwe@nih.gov
Phone:(301) 761-5038

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Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Dose Escalation Trial to Determine Safety and Development of Protective Efficacy After Exposure to Only Pre-erythrocytic Stages of Plasmodium Falciparum

Background:

People get malaria from bites from infected mosquitos. Researchers are studying a vaccine
strategy. They will give people malaria parasites by injecting them with live infectious
malaria parasites with antimalarial medications and then see if this strategy prevents
malaria infection while off antimalarial medications.

Objective:

To see if combining a high dose of live, infectious malaria parasites (known as Sanaria PfSPZ
Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine [PYR] OR
chloroquine [CQ]) is safe and can provide people protection against malaria.

Eligibility:

Healthy adults ages 18-50 who:

- are not pregnant or breastfeeding or planning on becoming pregnant while in the study

- are not infected with HIV, Hepatitis B or Hepatitis C

- have reliable early morning access to the NIH Clinical Center

- are able to come to the outpatient clinic frequently, sometimes daily

- have not been diagnosed with malaria within the past 10 years

Design:

- Participants will be screened with medical history and physical exam. They will have
heart, blood, and urine tests.

- Participants will have blood drawn for tests at most visits.

- Participants will keep track of their temperature and symptoms during some sections of
the study.

- Participants will join one part of the study.

Part 1 is one month:

- Participants will get the parasites by an injection into a vein on day 1 and receive
antimalarial medications.

- They will have daily visits on days 7-14

- They will take another antimalarial at visits on days 15-17.

- The final visit will be on day 29.

Part 2 is seven months:

- For the first 3 months, participants will get the parasite injection into a vein for 3
injections in total. Each injection will occur once per month while taking an
antimalarial drug.

- They will have daily visits on days 7-14 after the first injection, and on days 7-11
after the second and third injection.

- They will have a final (fourth) injection around month 6 without any antimalarial
medication.

- After this fourth injection, participants may have up to 21 daily visits from day 7
after injection until end of study.

Part 3 is one month:

- Participants will get the parasites by injection into a vein on day 1 without
antimalarial medications.

- They will have visits almost every day starting day 7 from injection.

- They will take an antimalarial medication when they are diagnosed with malaria

- They will return for final end of study visit on days 27-29.

Human studies have shown that immunization by the bite Plasmodium falciparum (Pf)
sporozoite(SPZ)-infected mosquitoes under drug coverage with chloroquine, an approach called
chemoprophylaxis with sporozoites (CPS) or infection treatment vaccination (ITV), can provide
high level, long term protection against homologous controlled human malaria infection
(CHMI). The Sanaria PfSPZ chemoprophylaxis vaccination (PfSPZ CVac) approach duplicates this
with an injectable SPZ regimen. In both approaches, whether mosquitoes or syringes are used
for SPZ administration, when chloroquine is used as the chemoprophylactic agent, transient,
limited, asexual erythrocytic stage is seen in the majority of participants. Thus the
question remains whether the significant protective efficacy seen can be achieved with
pre-erythrocytic (sporozoite/liver stage) exposure only.

Previously, we performed a phase 1 study to investigate the safety, tolerability,
immunogenicity, and protective efficacy of Sanaria PfSPZ CVac with chloroquine (sporozoites,
liver, and blood stage) or pyrimethamine with chloroquine (sporozoites and liver stage only)
to further describe stage specific sterile protection (NIAID protocol #15-I-0169). In this
study, we demonstrated that pyrimethamine is safe to administer, well tolerated, and can
prevent subpatent and patent parasitemia (qPCR and blood smear negative) 100% of the time
during Sanaria PfSPZ CVac. The study also duplicated the results previously reported with
Sanaria PfSPZ CVac with chloroquine in terms of safety profile and protective efficacy
against homologous CHMI. Although a combination of Sanaria PfSPZ- CVac with pyrimethamine and
PfSPZ Challenge at 51,200 PfSPZ did not provide a significant protection level against
homologous CHMI, we demonstrated that some subjects did develop protective immunity without
any evidence of blood stage exposure during PfSPZ-CVac.

Building on these results and taking the lessons learned from other pre-erythrocytic vaccine
studies and models that have shown the importance of reaching a minimal antigen threshold
required for the development of sterile immunity, this proposed study will assess the safety,
tolerability, immunogenicity, and protective efficacy of increasing the dose of Sanaria PfSPZ
Challenge sporozoites while receiving the same, or, if needed to successfully prevent
parasitemia, a higher dose of pyrimethamine. Unlike the first study, however, pyrimethamine
will be administered by itself as the partner drug, and will not be co-administered with
chloroquine. The efficacy of PfSPZ-CVac with pyrimethamine will be assessed against CHMI with
homologous parasites (Arm 2a) and CHMI with heterologous parasites (Arm 2b). Additionally, we
will explore the impact of increasing the dose of Sanaria PfSPZ Challenge sporozoites while
receiving chloroquine alone prophylaxis. The efficacy of PfSPZ-CVac with chloroquine will be
assessed only against CHMI with heterologous parasites (Arm 3), as protection against
homologous parasites has now been shown in two separate trials. It will thus be possible to
compare the efficacy of the two partner drugs against heterologous CHMI. The results of this
study will contribute to understanding the targets and mechanisms of immunity against Pf
malaria infection and how the degree of exposure to the parasite (pre-erythrocytic or
erythrocytic stage only or both) impacts these responses and subsequent protective efficacy.

- INCLUSION CRITERIA:

- Age greater than or equal to 18 and less than or equal to 50 years.

- In good general health and without clinically significant medical history

- Malaria comprehension exam completed, passed (a score of greater than or equal to 80%
or per investigator s discretion) and reviewed prior to enrollment

- Reliable access to the clinical trial center and availability to participate for
duration of study

- Females of childbearing potential must be willing to use reliable contraception (as
defined below) from 21 days prior to study day -2 to 28 days following last Sanaria
PfSPZ Challenge exposure

- Subject to the judgment and discretion of the PI, female participants who meet ANY ONE
of the criteria listed immediately below, may not be required to take any additional
measures to avoid pregnancy. Such participants will be counseled on risks at the time
of consent and at appropriate points (e.g. when pregnancy testing occurs) during the
study:

- Females who have had their uterus, and/or BOTH ovaries removed

- Females who have had BOTH fallopian tubes surgically 'tied' or removed

- Females who are above the age of 45 and have spontaneously had no menses at any
point during the past 12 or more consecutive months (i.e. have reached menopause)

- Females who, in the conservative and reasonable judgment of the PI (e.g. due to
sexual orientation or serious life choice (such as being celibate clergy or
transgender), during the entire trial will NOT participate in any potentially
reproductive sexual contact

- Females who, in the conservative and reasonable judgment of the PI, are in a
monogamous stable relationship with a male who has undergone vasectomy at least 4
months prior or another procedure/medical condition that deems the male sterile

- Subject to the judgment and discretion of the PI, female participants who DO NOT meet
ANY of the criteria listed above, will be appropriately counseled on reproductive
risks and pregnancy avoidance, and will be required to adhere to the following
measures and agree to 2 methods of pregnancy prevention as noted below:

- CATEGORY 1: a highly effective hormonal method to prevent pregnancy [e.g.
CONSISTENT, CONTINUOUS use of contraceptive pill, patch, ring, implant or
injection], and/or IUD or equivalent

- IN ADDITION TO CATEGORY 2: a barrier method to be used at the time of potentially
reproductive sexual activity (e.g. [male/female condom, 'cap,' or diaphragm] +
spermicide).

EXCLUSION CRITERIA:

- Currently is breast-feeding (if female).

- Pregnancy as determined by a positive urine or serum human choriogonadotropin (beta-
hCG) test at any point during the study (if female).

- Recent travel to a malaria endemic area within 5 years of enrollment (Endemic areas
are defined per the CDC website. Factors such as but not limited to use of antimalaria
prophylaxis during travel, length of stay, activities during the travel, history of
illnesses within 30 days of travel will be considered to determine the likelihood that
the subject was exposed to malaria)

- Planned travel to a malaria endemic area (as defined by the Center for Disease
Control) during the study period

- Reported history of confirmed malaria diagnosis on peripheral blood smear or by
clinical history in the past 10 years.

- Hemoglobin, WBC, platelets, ALT, and creatinine outside of local lab normal range
(subjects may be included at the investigator s discretion for not clinically
significant values outside of normal range)

- Abnormal urinalysis as defined by positive urine glucose, protein, and red blood
cells. Subject can be included if investigator determine the abnormality is not
clinically significant .

- BMI < 17 or BMI > 35

- Anticipated use during the study period, or use within the following periods prior to
enrollment:

- Investigational malaria vaccine within the last five years

- Malaria chemoprophylaxis within 6 months

- Chronic systemic immunosuppressive medications (>14 days) within 6 months
(e.g.cytotoxic medications, oral/parental corticosteroids >0.5 mg/kg/day
prednisone or equivalent). Corticosteroid nasal spray for allergic rhinitis and
topical corticosteroids for mild, uncomplicated dermatitis are allowed.

- Blood products or immunoglobulins within 6 months

- Systemic antibiotics with antimalarial effects within 30 days (such as
clindamycin, doxycycline)

- Investigational or non-registered product or vaccine within 30 days

- Receipt of a live vaccine within 28 days or a killed vaccine within the 14 days
prior to Sanaria PfSPZ Challenge

- Medications known to interact with pyrimethamine and/or chloroquine (for the main
and pilot study participants ONLY), atovaquone, proguanil (ALL participants)

- Reported history of:

- Sickle cell disease, sickle cell trait, or other hemoglobinopathies

- Splenectomy or functional asplenia

- Systemic anaphylaxis

- Any allergic reactions to study drugs (pyrimethamine, chloroquine) or NSAIDs,
atovaquone, proguanil

- Documented history of chronic or active neurologic disease (including seizures,
uncontrolled migraine headaches)

- Psoriasis or porphyria

- Ocular diseases including retinopathy or visual field defects

- Clinically significant medical condition, physical examination findings, other
clinically significant abnormal laboratory results, or past medical history that may
have clinically significant implications for current health status and participation
in the study in the opinion of the Investigator. A clinically significant condition or
process includes but is not limited to:

- A process that would affect the immune response, or requires medication that
affects the immune response

- Any contraindication to repeated phlebotomy

- A condition or process in which signs or symptoms could be confused with
reactions to malaria challenge and/or infection, including dermatologic
abnormalities at the site of sporozoite inoculation

- A chronic or subclinical condition which could be exacerbated by administration
of any of the PfSPZ-CVac components or malaria infection

- History of, or known active cardiac disease including: (1) prior myocardial infarction
(heart attack); (2) angina pectoris; (3) congestive heart failure; (4) valvular heart
disease; (5) cardiomyopathy; (6) pericarditis; (7) stroke or transient ischemic
attack; (8) exertional chest pain or shortness of breath; or ( 9) other heart
conditions under the care of a doctor

- Clinically significant ECG findings, as determined by the expert study cardiologist

- Moderate or high risk for coronary heart disease (CHD) based on NHANES I
cardiovascular risk assessment

- Acute illness at the time of enrollment

- Infection with HIV, Hepatitis B, Hepatitis C

- Psychiatric condition that precludes compliance with the protocol including but not
limited to:

- Psychosis within the past 3 years

- Ongoing risk for suicide, or history of suicide attempt or gesture within the
past 3 years

- Suspected or known current alcohol or drug abuse as defined by the American
Psychiatric Association in the DSM V at the discretion of the PI

- Clinical trial staff and/or Sanaria Inc. employees with direct involvement in the
conduct of the trial are excluded from participation.

- Participating in other clinical trials involving investigational interventions or off
label medication use during the study period (excluding participation in the optional
long term follow up visits). Participation in other trials such as observational or
imaging studies will be discussed with the investigators.

- Any other finding that, in the judgment of the Investigator, would interfere with, or
serve as a contraindication to, protocol adherence, assessment of safety or
reactogenicity, or a subject s ability to give informed consent, or increase the risk
of having an adverse outcome from participating in the study.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
301-496-2563
Phone: 800-411-1222
National Institutes of Health Clinical Center The National Institutes of Health (NIH) Clinical Center in...
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mi
from
Bethesda, MD
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